CD39. also known as ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), is a cell membrane-bound enzyme that plays a key role in purinergic signaling by hydrolyzing extracellular ATP and ADP into AMP. This process ultimately leads to the generation of immunosuppressive adenosine via the sequential activity of CD73. CD39 is expressed on various immune cells, including regulatory T cells (Tregs), dendritic cells, and tumor-infiltrating lymphocytes, as well as certain cancer cells. Its enzymatic activity contributes to the establishment of an immunosuppressive microenvironment, particularly in tumors, by dampening pro-inflammatory ATP signaling and promoting adenosine-mediated immune suppression.
CD39 antibodies are investigative tools and therapeutic agents designed to target this pathway. By blocking CD39’s enzymatic function, these antibodies aim to reduce adenosine accumulation, enhance ATP-driven pro-inflammatory responses, and counteract immune evasion in diseases like cancer. Preclinical studies suggest that CD39 inhibition can synergize with other immunotherapies, such as anti-PD-1/PD-L1 agents, to improve antitumor immunity. Additionally, CD39 antibodies are explored for modulating autoimmune and inflammatory conditions where purinergic signaling dysregulation is implicated. Research continues to clarify their dual role in either agonizing or antagonizing CD39 activity, depending on antibody specificity and disease context. Current efforts focus on optimizing antibody design and evaluating clinical efficacy in ongoing trials.